The present invention relates to a dosage form that provides a controlled release of sertraline to an environment of use.
Sertraline is a selective serotonin reuptake inhibitor which is useful, inter alia, as an antidepressant and anorectic agent, and in the treatment of obsessive-compulsive disorder, premenstrual dysphoric disorder, post-traumatic stress disorder, chemical dependencies, anxiety-related disorders, panic and premature ejaculation. See, for example, U.S. Pat. Nos. 4,536,518, 5,130,338, 4,971,998, 5,061,728, 4,940,731, and 4,962,128. The IUPAC name for sertraline is (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, its empirical formula is C12H17NCl2, and its structural formula is 
Sertraline is most commonly prescribed for therapy of depressive illness, in the general dose range 50-200 mgA/day wherein “mgA” refers to active sertraline in the free base, or neutral form. Sertraline has an elimination half-life of 23 hours, and is conventionally dosed once daily with immediate-release tablets.
Patients are generally initiated on sertraline at a dose of 50 mgA/day or less. Patients who do not respond at the 50 mgA dose are given higher doses. Initiation at doses greater than 50 mgA is generally avoided, when possible, because side effects such as dizziness, tremor, sweating, and gastrointestinal upset are generally believed to be more severe at higher doses. If necessary to achieve efficacy, higher doses may be reached by gradual increases in dosage.
Improved sertraline dosage forms which exhibit a lower incidence and/or severity of side effects would be advantageous because patient comfort and thus, compliance, would be improved and dosing could be initiated at doses higher than 50 mgA without the need for gradual increases. Initiation at higher starting doses would, in turn, be useful by potentially effecting a shorter onset of antidepressive action. Thus, such an improved sertraline dosage form which permits oral dosing of high doses of sertraline (e.g., 60 mgA and higher) with relatively reduced side effects would permit wider therapeutic application of sertraline therapy, and would accordingly provide a significant improvement in dosing compliance and convenience. Similarly, a dosage form which lowers the incidence and/or severity of side effects at lower doses would also be of significant value.
While such a once-a-day dosage form with reduced incidence or severity of side effects at a given dose is desirable, there are practical difficulties attendant to the development of such a dosage form. There is an upper limit on the size a dosage form may take. It is desired that a dosage form have a mass of less than 1 g, preferably less than about 800 mg, and more preferably no more than about 600 mg. In some cases, particularly when treating children or elderly patients, even lower mass tablets are desirable. Otherwise, the dosage form becomes so large that it is difficult to swallow.
The sertraline dose in an individual dosage form must be about 20 to 200 mgA, and preferably about 40 mgA to 150 mgA. This amount of active sertraline requires that an amount of sertraline salt (e.g., chloride, lactate, acetate, aspartate) be included in the core such that the desired amount of active agent is delivered. Assuming complete release of the drug, this means that to deliver 150 mgA, the core must contain 168 mg sertraline chloride, 194 mg sertraline lactate, 215 mg sertraline aspartate, or 179 mg sertraline acetate. Because sertraline occupies such a large portion of the core, the remaining excipients must be capable of providing the desired release profile using a minimum amount of material. Although this is most true at higher dose levels, it is often desirable to have a range of dosage forms that vary in dose with their size, but have a common composition. Thus, the tablet composition can be limited by the magnitude of the highest dose tablet.
Sertraline also has poor aqueous solubility, particularly at pH values above 6 to 7. This can result in low bioavailability, where bioavailability is the fraction of drug orally dosed that is absorbed into the blood stream, particularly in controlled-release dosage forms. Bioavailability from controlled release sertraline formulations can be significantly less than 100%, particularly at high drug doses and when a significant portion of the drug is delivered in the lower GI tract where the pH is relatively high and drug solubility is relatively low. While the solubility of sertraline is relatively high at low pH, e.g., 6 mgA/mL at pH 2.0, the solubility is much lower at higher pH. Thus, at a pH of 6.5 (generally corresponding to the pH in the duodenum), the solubility of sertraline is only about 1 mgA/mL, while at a pH of about 7.0 (generally corresponding to the pH of the small intestine), the solubility is about 0.2 mgA/mL, while at a pH of about 7.5 (generally corresponding to the pH in the colon), the solubilty is about 0.05 mgA/mL. While the lower pH in the stomach is ideal for solubilizing sertraline, it has been found that the incidence or severity of side effects such as nausea can be minimized by avoiding the release of excessive sertraline within the stomach. Thus, while the solubility of sertraline in the stomach is high, it is desired to limit the amount of sertraline released into the stomach to an acceptable level. However, the steadily decreasing solubility of sertraline as it proceeds down the GI tract (as pH increases) can result in low bioavailability if release is delayed too long.
As a result, to achieve the combined goals of (1) reduced incidence or severity of side effects (e.g., nausea), (2) high bioavailability, and (3) therapeutic blood levels over as long a time period as possible, a narrow range of drug release profiles is desired, which not only limits the amount of sertraline released into the stomach to an acceptable level, but also provides good absorption of sertraline either by (1) insuring that most of the sertraline is delivered prior to reaching the colon, or (2) delivering sertraline to the colon in such a manner that it is substantially absorbed. In addition, because the dose of sertraline may be high (e.g., 100 mgA to 200 mgA) and it is ideal to deliver a single tablet each day, it is desired that the dosage form deliver a substantial amount of the drug, leaving relatively low residual drug and that the amount of drug be a high fraction of the overall weight of the dosage form.
Under certain conditions, and in the presence of certain excipients used for formulation of conventional controlled-release dosage forms, sertraline may undergo adverse reactions that can alter its bioavailability or lead to undesirable impurities within a relatively short time, thus giving it a poor shelf life. Commercially acceptable controlled release dosage forms must provide patients with all of the desired attributes mentioned above while providing patients with a supply of sertraline that may be stored for relatively long periods of time and over a reasonably wide range of temperature and humidity conditions and still remain stable.
It is known that osmotic and hydrogel delivery devices of a bi-layer design, having a drug-containing composition and a water-swellable composition, may be used to provide controlled release of drugs through a surrounding coating having one or more delivery ports in the coating. However, a common problem encountered by such osmotic and hydrogel dosage forms is that residual drug remains within the dosage form after the dosage form exits that portion of the GI tract where drug absorption occurs. Such residual drug is not available for absorption and, accordingly, such dosage forms require increased amounts of drug to compensate for the failure of the dosage form to deliver all of the drug into the environment of use. In addition, the amount of such residual drug can be variable and may lead to variability of sertraline blood levels from patient to patient and from day to day.
Such bi-layer osmotic and hydrogel devices by definition contain water-swellable materials that occupy significant space within the core that otherwise would be available for sertraline. The water-swellable materials that provide delivery of the drug must be capable of providing a highly efficient delivery of sertraline, since very little of the mass of the dosage form may be available for the water-swellable material.
In addition, to maximize the bioavailability of the drug it is often desirable to have the dosage form begin delivery of sertraline immediately upon entering an aqueous environment of use. However, many bi-layer delivery systems exhibit a time lag before the onset of drug delivery. Several techniques have been proposed to overcome the time lag, but each has its own drawback. One technique has been to provide thin coatings around the dosage form. While this technique provides a quicker uptake of aqueous fluid, the thin coating often provides insufficient protection to the dosage form which becomes susceptible to damage during handling. Such thin coatings are also inherently weak and upon ingestion can rupture, causing uncontrolled release of drug. Yet another technique for eliminating the delivery time lag has involved providing holes or channels that allow communication of the water-swellable composition with the exterior fluid, but this often leads to unacceptable amounts of residual drug. Another technique involves coating the core with an immediate release drug formulation, but this requires additional processing steps, and is problematic in that the drug is often not stable in such coatings.
Yet another problem encountered with conventional bi-layer osmotically-driven and hydrogel-driven drug delivery systems is that conventionally such dosage forms require the presence of osmagents. These osmagents are often necessary, particularly when low water permeability coatings are used, to increase the drug release rate, but have the drawback of increasing the weight of the dosage form, thus further limiting the amount of sertraline which may be contained in the dosage form. Another drawback of inclusion of an osmagent is that it can potentially interact adversely with sertraline, thereby accelerating its degradation (in the case of certain sugars) or reducing its dissolution (in the case of salts such as chlorides). In addition, the presence of such osmagents increases the costs of manufacture due to the need to insure uniform concentrations of such ingredients throughout the composition.
Sustained and delayed release dosage forms of sertraline as well as a variety of sertraline compositions have been disclosed in commonly assigned U.S. patent application Ser. No. 09/380,885 filed Sep. 7, 1999 now abandoned, U.S. patent application Ser. No. 09/380,825 filed Sep. 7, 1999, and U.S. patent application Ser. No. 09/380,900 filed Sep. 7, 1999. However, none of these disclose a dosage from where the drug is in the form of an amorphous dispersion or a bi-layer osmotic dosage form that permits high drug loading, stability and optimum drug release profiles, and high bioavailability, all of which are possible with the present invention.
In addition, a variety of bi-layer osmotic and hydrogel-driven devices for many different drugs have been disclosed. See, e.g. Wong et al., U.S. Pat. No. 5,082,668; Eckenhoff, U.S. Pat. No. 4,865,598; Courtese et al., U.S. Pat. No. 4,327,725; and Ayer et al., U.S. Pat. No. 5,126,142. Nonetheless, the prior art bi-layer dosage forms do not disclose the means by which sertraline, a poorly soluble, hydrophobic, and potentially reactive drug, may be optimally delivered to a use environment in a controlled release fashion.
Accordingly, there is still a need in the art for a controlled release dosage form of sertraline that results in a highly efficient delivery of sertraline to an environment of use with very little residual drug, that allows high drug loading so as to decrease the dosage form size, that begins delivering drug soon after entering a desired environment of use, that limits the number of other components in the dosage form, that reduces the frequency or severity of negative side effects by limiting the release of sertraline to the stomach to an acceptable level, and that simultaneously achieves high bioavailability. Obtaining such high bioavailability may require that either the sertraline release profile be carefully controlled so that substantially complete release is achieved prior to entering the colon or, when delivery is continued in the colon, modifying the material released such that the absorption of sertraline in the colon is enhanced. These needs and others which will become apparent to one skilled in the art are met by the present invention, which is summarized and described in detail below.